Peripheral nerve injury triggers the activation of the small GTPase RhoA in spinal motor and peripheral sensory neurons. C3 transferase, an exoenzyme produced by Clostridium botulinum that inactivates RhoA by ADP-ribosylation, has been successfully applied in central nervous system (CNS) lesion models to facilitate regeneration functionally and morphologically. Until now it has not been demonstrated if C3bot exerts positive effects on peripheral axon regeneration as well. In organotypic spinal cord preparations, C3bot reduced axonal growth of motoneurons, while no effect on sensory axon outgrowth from dorsal root ganglia (DRG) explants was observed. Enzymatically inactive C3E174Q was ineffective in both culture models. Spinal cord slices exhibited a significant increase in microglia/macrophages after treatment with C3bot suggesting an inflammatory component in the inhibition of axon growth. C3bot or C3E174Q were then applied into conduits implanted after transection of the sciatic nerve in rats. Functional evaluation by electrophysiology, nociception, and walking track tests did not show any significant difference between groups with active or mutant C3E174Q . Transmission electron microscopy of the regenerated nerves revealed no significant differences in the number of myelinated and unmyelinated axons 6 weeks after surgery. Compared to the CNS, the functional significance of RhoA may be limited during nerve regeneration in a growth-promoting environment.

译文

:周围神经损伤触发脊髓运动和周围感觉神经元中小GTPase RhoA的激活。 C3转移酶是由肉毒梭菌产生的一种外切酶,可通过ADP-核糖基化使RhoA失活,已成功应用于中枢神经系统(CNS)病变模型中,以促进功能和形态上的再生。到目前为止,尚未证明C3bot是否也对外周轴突再生产生积极作用。在器官型脊髓制剂中,C3bot减少了运动神经元的轴突生长,而未观察到背根神经节(DRG)外植体对感觉轴突生长的影响。在两种培养模型中,无酶活性的C3E174Q均无效。用C3bot处理后,脊髓切片显示出小胶质细胞/巨噬细胞的显着增加,表明炎性成分可抑制轴突的生长。然后将C3bot或C3E174Q应用于大鼠坐骨神经横切后植入的导管中。通过电生理学,伤害感受和步行试验的功能评估未显示具有活性或突变C3E174Q的组之间的任何显着差异。再生神经的透射电子显微镜显示,术后6周有髓和无髓轴突的数量没有显着差异。与CNS相比,RhoA的功能意义可能在促进生长的环境中的神经再生过程中受到限制。

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